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关键词： cancer   inflammation   VDAC   cGAS   STING  

摘要： Identification of therapeutic vulner-abilities in cancer remains a high priority for cancer research. A re-cent CRISPR/Cas9 screen identified that VDAC2 deletion in tumors enhanced their sensitivity to interferon-gamma(IFN gamma) through the release of mitochondrial DNA (mtDNA) and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) path-way. These data suggest that VDAC2 inhibition could enhance antitumor therapies.

摘要： Cocaine dysregulates tumor necrosis factor (TNF) signaling in mesolimbic substrates, suggesting a role for TNF in cocaine-induced hyperlocomotion, a signature preclinical effect of cocaine. Inhibition of TNF signaling by genetic deletion or with a brain-penetrable TNF antagonist enhances cocaine-induced hyperlocomotion in male mice, but roles for sex and peripheral TNF are unclear. Also unknown is how peripherally restricted etanercept, the world's most widely prescribed TNF inhibitor, affects cocaine-induced locomotor responses. We determined effects of etanercept on a triad of cocaine-induced locomotor responses (e.g., ambulation, stereotypy, distance traveled) in male and female rats and impacts of etanercept-cocaine exposure on tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA levels in the ventral tegmental area (VTA). Etanercept (20 mg/kg, IP) and a submaximal dose of cocaine (10 mg/kg, IP) were used initially, and etanercept was injected 48 h before cocaine to capture peak plasma concentrations. Etanercept itself did not affect spontaneous locomotor responses in male or female rats. In male rats, etanercept increased cocaine-induced ambulatory and stereotypical activities and enhanced cocaine-induced distance traveled. Etanercept modestly reduced TH mRNA levels in the VTA of cocaine-na & iuml;ve and cocaine treated male rats. Locomotor responses in male rats that were evoked by a higher dose of cocaine (20 mg/kg, IP) were not affected by etanercept. In female rats, etanercept did not affect any cocaine-induced locomotor responses. These results show that etanercept exerts effects on locomotor behaviors induced by cocaine that depend on both sex and cocaine dose and suggest that peripheral inhibition of TNF influences cocaine-induced behaviors. Key words: etanercept;TNF;cocaine;dopamine;tyrosine hydroxylase;DAT;locomotor.

摘要： IntroductionTo evaluate the predictive value of combined determination of peripheral neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), C-reactive protein (CRP) and interleukin-6 (IL-6) in the treatment of adamylizumab in patients with ankylosing spondylitis (AS). MethodFrom January 2020 to May 2024, 60 patients with AS in our hospital were selected and treated with adalimumab for 12 weeks. The changes of NLR, PLR, CRP, IL-6 levels before and after treatment were compared, and the improvement of the disease was assessed by BASMI spinal activity, and the patients were divided into ineffective group (BASMI>4 points) and effective group (BASMI≤4 points). The correlation between Spearman and BASMI was analyzed, and the predictive value was analyzed by ROC curve. ResultsAfter treatment, the scores of NLR, PLR, CRP, IL-6 and BASMI were decreased compared with those before treatment (P<0.05). The levels of NLR, PLR, CRP and IL-6 were positively correlated with BASMI (P<0.05). Before treatment, the indexes in the ineffective group were higher than those in the effective group (P<0.05). The combined prediction AUC is 0.664. DiscussionThe combined determination of NLR, PLR, CRP and IL-6 in peripheral blood can predict the therapeutic effect of adalimumab in patients with AS.

关键词： A20   CYLD   myeloproliferative neoplasms   SHP   STATs   HLA  

摘要： Myeloproliferative neoplasms, encompassing essential thrombocythemia, primary myelofibrosis, and polycythemia vera, represent a subset of hematological disorders within the Philadelphia-negative subgroup. The molecular network involved in the JAK/STATs signaling pathway has been demonstrated involved in the genetic landscape of Myeloproliferative disorders in several studies. Deubiquitinating genes such as CYLD and A20 are known as negative regulators of immune reactions. In this study, we assessed the expression levels of CYLD, A20, SHPs, and STATs genes by q-PCR. Additionally, genotyping via Kompetitive Allele Specific PCR (KASP) was employed to discern the genotypes of 5 variants within the A20, JAK2, HLA, and OR10Q2P genes. Furthermore, levels of inflammatory cytokines and cancer antigen 125 (CA-125) were quantified using enzyme-linked immunosorbent assay (ELISA). Results showed that mRNA levels of CYLD,A20 and SHP-1 were significantly lower in all Myeloproliferative neoplasms patients, while expressions of SHP-2,STAT1 and STAT6 were significantly enhanced in Essential thrombocythemia patients when compared to controls. Concentrations of inflammatory cytokines IL-6, TNF-alpha, IL-1 beta as well as the cancer antigen protein CA-125 were elevated in Myeloproliferative neoplasms cases. Genotyping results explored that rs10974947 in JAK2, rs200878487 in A20, and rs2281389 in HLA had higher frequencies in PMF cases compared to controls. Importantly, two novel associations as our knowledge, between the variant HLArs2281389 (p = 0.004, OR = 2.6, 95% CI = 1.36-4.85) and OR10Q2P rs12289961 - a LPXN-nearby variant (OR = 1.95, 95%CI = 1.01-3.75) with Polycythemia vera were detected in this studied population. These data suggested that A20, JAK2,HLA and LPXN genes may have important functions in disease phenotypes. Nevertheless, further functional studies on these genes should be carried out for a better understanding of Myeloproliferative neoplasms pathogenesis.

关键词： Long-COVID   T cells   Cytokines   IL-3  

摘要： Following SARS-CoV-2 infection, some individuals develop Long-COVID-syndrome lasting for more than 3 months. We analyzed blood samples from patients with Long-COVID, controls without persistent symptoms following SARS-CoV-2-infection and non-infected donors without a history of infection. Long-COVID patients showed clear signs of T cell hyper-activation predominantly in the CD8+ T cell subset with a 4-fold higher expression of CD25 and 2-fold more effector-memory T cells. Following polyclonal T cell stimulation, we found a 2-fold stronger upregulation of CD25 and a 7-fold higher release of IL-3 in Long-COVID. Intracellular staining revealed 5-fold more IL-3-expressing CD8+ T cells in Long-COVID, while GM-CSF, IFN-gamma and IL-2 were much less upregulated. These changes correlated with the severity of Long-COVID and persisted for up to 18 months after infection. Our data reveal a pronounced and long-lasting CD8+ T cell hyper-activation and hyper-reactivity in Long-COVID and speak for a trial of T cell-immunosuppression in patients with Long-COVID.